This study will evaluate an innovative program for smokers with Post-Traumatic Stress Disorder (PTSD) that integrates the most effective medication for smoking cessation (varenicline) with prolonged exposure (PE), a highly efficacious cognitive behavioral therapy for PTSD. The development of specifically tailored and more efficacious smoking cessation treatments for smokers with psychiatric disorders, whose cigarette smoking is disproportionately high, has been identified as a high priority in public health policy. PTSD is a common mental disorder with a lifetime prevalence of 6.8%. The prevalence of smoking in people with current PTSD is 44.6% -- double the rate of those with no history of a psychological disorder (22.5%). Smokers with PTSD are more likely to be nicotine dependent, smoke heavily, experience more severe withdrawal symptoms, and relapse after a quit attempt. In fact, the quit rate for smokers with PTSD is among the lowest compared to other mental disorders. Factors that may contribute to smokers' progression to nicotine dependence and relapse include negative affect, fear, anxiety sensitivity, increased arousal, irritability, and anger. Therefore, the integration of treatment for smoking cessation with treatment for PTSD that reduces these factors is hypothesized to improve success of smoking cessation about smokers with PTSD. To test this hypothesis, we will randomly assign smokers with PTSD to either the best practice pharmacotherapy for smoking cessation (varenicline) alone or to a treatment that integrates varenicline with PE. The primary outcome measure will be biochemically confirmed abstinence rates at the end of treatment and at follow-up 6-months post quit date. Secondary outcome measures will be continuous abstinence, prolonged abstinence, and time to relapse. We will also obtain measures of PTSD and associated psychopathology (e.g. depression and anxiety) and risk factors (e.g. anxiety sensitivity). Collectively, our research group has expertise in the development of efficacious treatments for PTSD, including PE (Foa, Cahill, Hembree), the epidemiology of smoking and psychiatric disorders (Breslau), and smoking cessation (Lerman, O'Brian, Gariti). The proposed research affords a unique opportunity to combine experts from diverse areas with the aim of developing an innovative, integrated approach to the treatment of people who are likely to fail using existing treatments. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the single most preventable cause of premature death in the US; approximately 50% of long-term smokers die of a disease caused by their dependence, shortening lives by an average of 13-14 years. Smokers with Post Traumatic Stress Disorder (PTSD) are more likely to be nicotine dependent, to smoke heavily (25 cigarettes per day or more), experience more severe withdrawal symptoms, and relapse following a quit attempt than smokers without PTSD. In this grant application, we propose to evaluate an innovative treatment program for smokers with PTSD that integrates varenicline, the most effective medication for smoking cessation, with prolonged exposure therapy, a highly effective form of psychotherapy for PTSD.